Echinocandin B is a natural product with antifungal activity that has been modified in the past in a variety of ways. For example, simple derivatives have been made including dihydro- and tetrahydro-reduction products and modification of active groups pendant from the ring nucleus. The most common approach has been replacement of the N-acyl side chain. For example, U.S. Pat. Nos. 4,293,489; 4,320,052; 5,166,135; and 5,541,160; and EP 359529; 448353; 447186; 462531; and 561639 describe a variety of N-acyl derivatized Echinocandin-type compounds that provide varying degrees of antifungal and antiprotozoal activities.
Other modifications have included acylation of the hydroxyl group of the pendant phenolic group. For example, GB 2,242,194; and EP 448343; 448354; 503960 and 525889 describe the introduction of acyl, phosphono and sulfo radicals having a charged group at neutral pH to impart water solubility.
GB 2,241,956 and EP 448355 describe hydrogen-reduction products of cyclohexapeptide compounds.
A review of the Echinocandin families and their semi-synthetic analogs may be found in Turner, W., et al, Current Pharmaceutical Design, 2, 209-224 (1996). The review compares the in vitro and in vivo activities of the Echinocandin natural products and their semi-synthetic analogs.
Each of the approaches described above are limited to reactions with active groups pendant to the cyclic peptide ring nucleus. Some have attempted to build the entire cyclic peptide nucleus synthetically. (See, i.e., U.S. Pat. No. 5,696,084; J. Am. Chem. Soc., 108, 6041 (1986); Evans, D. A., et al., J. Am. Chem. Soc., 109, 5151 (1987); J. Med. Chem., 35, 2843 (1992); and Kurokawa, N., et al., Tetrahedron, 49, 6195 (1993).) However, this approach is not cost effective and may lead to racemic mixtures. Therefore, there is a need to provide a more flexible and cost effective process for modifying the cyclic hexapeptide nucleus of natural products to broaden the scope of potential antifungal candidates.
Several investigators have disclosed the preferential cleavage of an amide bond in compounds bearing hydroxyl groups in the delta and gamma positions relative to the amide bond to provide asymmetric lactones using acids such as hydrochloric acid and trifluoroacetic acid; however, none have applied the process to the cleavage of a terminal amino acid group of a linear peptide. (See, i.e., K. Tanaka, et al., Tetrahedron Lett, 26(10), 1337 (1985); N. Baba, et al., Chem Lett (5), 889 (1989); H. Yoda, et al, Chem Express, 4(8), 515 (1989); and Y. Yamamoto, et al., J Org Chem, 56(3), 112 (1991).)